Synthesis of Novel C-Pivot Lariat 18-Crown-6 Ethers and Their Efficient Purification

Abstract

The syntheses of various lariat ethers including several not previously reported and their efficient purification are presented. The synthesis route brings together reactions from a variety of previous works leading to a robust and generalized approach to these C-pivot lariats. The main steps are condensation of functionalized diols with pentaethylene glycol ditosylate in the presence of potassium as a templating cation. Purification of the final products was achieved without chromatography by extracting from an aqueous potassium hydroxide solution.

Key words

18-crown-6 - C-pivot lariat ethers - crown compounds - potassium hydroxide purification - macrocyles

• References and Notes

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• 19 General Procedure for the Synthesis of Benzyl-Protected 18-C-6 Lariat Ethers 1c–7c To a solution of benzylated diol 1b–7b (25 mmol) in THF (240 mL) was added KOt-Bu (100 mmol) at r.t. After the mixture was allowed to react 1 h under a nitrogen atmosphere, a solution of pentaethylene glycol ditosylate (27.5 mmol) in THF (48 mL) was added over a period of 1 h with stirring. The mixture was stirred for an additional 1 h at r.t., refluxed for 24 h, and cooled to r.t. The volatile solvents were removed by distillation under reduced pressure. The crude solids were dissolved in H₂O, and the resulting solution was extracted with CH₂Cl₂ (5 × 20 mL). The combined organic layer was dried over anhydrous Na₂SO₄. After filtration and evaporation, the crude product (approx. 3.5 g) was directly used for the debenzylation in the next step.
• 20 General Procedure for the Synthesis of 18-C-6 Lariat Ethers 1d–7d To a dry round-bottom flask was added 10% (w/w) of 5% Pd/C and anhydrous EtOH (200 mL) was added to the reaction flask. The solution was degassed by bubbling the H₂ gas through it twice. Benzylated lariat ethers 1c–7c (approx. 3.5 g) dissolved in anhydrous EtOH (20 mL) was added into the reaction flask. The solution was degassed twice. The reaction mixture was stirred for 48 h under 1.013 bar of hydrogen. TLC with alumina plates using 4% 2-PrOH–CH₂Cl₂ as the eluent indicated the formation of product (R_f = 0.15). The product mixture was filtered and concentrated. The crude reaction mixture was then stirred into KOH aq (1 M, 50 mL) for 5 min. After this time, the impurities were removed by extraction using EtOAc until TLC showed the absence of any impurity (usually three extractions). The H₂O layer was then extracted with CH₂Cl₂ (3 × 20 mL, monitored by alumina TLC; 4% 2-PrOH–CH₂Cl₂ eluent). The organic layer was collected, the solvent was removed in vacuo, and the resulting material was passed through a small plug of neutral alumina (10% MeOH–EtOAc as eluent) to furnish noncomplexed lariat products. 2-Hydroxymethyl-18-C-6 (1d) ^2a–g Obtained in 65% yield (1.74 g) as a colorless viscous oil. ¹H NMR (400 MHz, CDCl₃): δ = 2.93 (s, 1 H, OH), 3.46–3.82 (m, 25 H, 12 × CH₂ and 1 × CH). ¹³C NMR (100 MHz, CDCl₃): δ = 63.0 (CH₂OH), 69.6 (CH₂O), 70.6 (CH₂O), 70.7 (CH₂O), 70.75 (2 × CH₂O), 70.8 (CH₂O), 70.83 (CH₂O), 71.0 (CH₂O), 71.03 (CH₂O), 71.2 (CH₂O), 71.8 (CH₂O), 79.4 (CH). ESI-HRMS: m/z [M + H] calcd for C₁₃H₂₆O₇: 295.1757; found: 295.1751. 2-[Hydroxy-(ethoxymethyl)]-18-C-6 (2d) Obtained in 60% yield (1.66 g) as a colorless viscous oil. ¹H NMR (400 MHz, CDCl₃): δ = 2.84 (s, 1 H, OH), 3.50–3.84 (m, 29 H, 14 × CH₂ and 1 × CH). ¹³C NMR (100 MHz, CDCl₃): δ = 61.8 (CH₂OH), 69.8 (CH₂O), 70.7 (CH₂O), 70.73 (CH₂O), 70.77 (CH₂O), 70.8 (CH₂O), 70.83 (CH₂O), 70.9 (CH₂O), 70.95 (CH₂O), 71.0 (CH₂O), 71.1 (CH₂O), 71.13 (CH₂O), 71.4 (CH₂O), 72.7 (CH₂O), 78.3 (CH). ESI-HRMS: m/z [M + H] calcd for C₁₅H₃₀O₈: 339.2019; found: 339.2017. 2-[Hydroxy-(ethoxy)-(ethoxymethyl)]-18-C-6 (3d) Obtained in 55% yield (1.56 g) as a colorless viscous oil. ¹H NMR (400 MHz, CDCl₃): δ = 2.76 (s, 1 H, OH), 3.47–3.81 (m, 33 H, 16 × CH₂ and 1 × CH). ¹³C NMR (100 MHz, CDCl₃): δ = 61.8 (CH₂OH), 69.9 (CH₂O), 70.4 (CH₂O), 70.6 (CH₂O), 70.7 (2 x CH₂O), 70.73 (CH₂O), 70.76 (CH₂O), 70.8 (CH₂O), 70.9 (2 × CH₂O), 70.93 (CH₂O), 71.0 (CH₂O), 71.4 (CH₂O), 71.5 (CH₂O), 72.6 (CH₂O), 78.3 (CH). ESI-HRMS: m/z [M + H] calcd for C₁₇H₃₄O₉: 383.2281; found: 383.2276. 2-Hydroxyethyl-18-C-6 (4d) Obtained in 50% yield (1.35 g) as a colorless viscous oil. ¹H NMR (400 MHz, CDCl₃): δ = 1.65–1.85 (m, 2 H, CH₂), 3.01 (s, 1 H, OH), 3.58–3.75 (m, 22 H, 11 × CH₂), 3.75–3.90 (m, 3 H, 1 × CH₂ and 1 × CH). ¹³C NMR (100 MHz, CDCl₃): δ = 34.8 (CH₂), 60.1 (CH₂OH), 69.4 (CH₂O), 70.6 (CH₂O), 70.7 (CH₂O), 70.77 (CH₂O), 70.8 (CH₂O), 70.86 (CH₂O), 70.9 (CH₂O), 71.0 (CH₂O), 71.05 (CH₂O), 71.7 (CH₂O), 74.5 (CH₂O), 77.7 (CH). ESI-HRMS: m/z [M + H] calcd for C₁₄H₂₈O₇: 309.1913; found: 309.1908. 2-Hydroxypropyl-18-C-6 (5d) ^2h Obtained in 48% yield (1.31 g) as a colorless viscous oil. ¹H NMR (400 MHz, CDCl₃): δ = 1.51–1.68 (m, 4 H, 2 × CH₂), 2.30 (s, 1 H, OH), 3.50–3.76 (m, 24 H, 12 × CH₂), 3.83–3.88 (m, 1 H, 1 × CH). ¹³C NMR (100 MHz, CDCl₃): δ = 28.5 (CH₂), 28.9 (CH₂), 62.8 (CH₂OH), 69.6 (CH₂O), 70.6 (CH₂O), 70.68 (CH₂O), 70.7 (CH₂O), 70.9 (2 x CH₂O), 70.91 (CH₂O), 70.92 (CH₂O), 70.94 (CH₂O), 71.0 (CH₂O), 74.2 (CH₂O), 79.0 (CH). ESI-HRMS: m/z [M + H] calcd for C₁₅H₃₀O₇: 323.2070; found: 323.2064. 2-Hydroxybutyl-18-C-6 (6d) Obtained in 45% yield (1.24 g) as a colorless viscous oil. ¹H NMR (400 MHz, CDCl₃): δ = 1.26–1.62 (m, 6 H, 3 × CH₂), 2.48 (s, 1 H, OH), 3.62–3.74 (m, 24 H, 12 × CH₂), 3.80–3.85 (m, 1 H, 1 × CH). ¹³C NMR (100 MHz, CDCl₃): δ = 21.9 (CH₂), 31.5 (CH₂), 32.9 (CH₂), 62.7 (CH₂OH), 69.5 (CH₂O), 70.67 (4 × CH₂O), 70.7 (CH₂O), 70.8 (CH₂O), 70.9 (CH₂O), 71.0 (CH₂O), 71.1 (CH₂O), 74.3 (CH₂O), 79.3 (CH). ESI-HRMS: m/z [M + H] calcd for C₁₆H₃₂O₇: 337.2226; found: 337.2221. 1,2-Dihydroxymethyl-18-C-6 (7d) ^2l Obtained in 55% yield (1.24 g) as a colorless viscous oil. ¹H NMR (400 MHz, CDCl₃): δ = 2.60 (s, 1 H, OH), 3.44 (s, 1 H, OH), 3.59–3.84 (m, 26 H, 12 × CH₂ and 2 × CH). ¹³C NMR (100 MHz, CDCl₃): δ = 61.8 (2 × CH₂OH), 70.2 (2 × CH₂O), 70.3 (2 × CH₂O), 70.5 (2 × CH₂O), 70.9 (2 × CH₂O), 70.91 (2 × CH₂O), 80.7 (2 × CH). ESI-HRMS: [M + H] calcd for C₁₄H₂₈O₈: 325.1862; found: 325.1857.